Myelodysplastic syndromes (MDS) are acquired clonal disorders of hematopoietic progenitors that are characterized by peripheral cytopenias and cytologic dysplasias (Greenberg et al., 1997). There is a strong association between bone marrow failure and autoimmunity that transects classical autoimmune processes such as aplastic anemia, rheumatoid arthritis, Felty's Syndrome, and large granular lymphocyte (LGL) leukemia (Colmegna et al., 2008; Loughran, Jr., 1998; Starkebaum et al., 1997). Similar to these quintessential autoimmune bone marrow failure syndromes, hematopoietic suppression by a T-cell dominant autoimmune process and IST responsiveness has been proposed in younger MDS patients. In MDS cases where hematologic improvement is observed after IST, the response can be durable leading to improved long-term survival (Lim et al., 2007; Molldrem et al., 1997; Biesma et al., 1997). Despite a clear therapeutic benefit and a basic understanding of immune pathology, IST is rarely offered to MDS patients as a treatment option in the United States due to an uncertainty about the appropriate selection of patients for such therapy (Steensma & Tefferi, 2003). There is an underlying concern that inappropriate use of IST may negatively impact risk for leukemia progression, which occurs in 30-40% of MDS cases. This is of particular concern in younger patients that may benefit from allogeneic stem cell transplantation (List et al., 2004). The identification of immunological factors in addition to younger age to guide appropriate selection of patients for IST based on immune pathobiology is critical to the optimization of MDS treatment.
In MDS patients of younger age, a higher frequency of clinical responsiveness to immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and/or cyclosporine-A (CyA) suggests that unique immune pathobiology contributes to the refractory cytopenias observed in such patients. Factors associated with response to IST included HLA-DR-15 genotype, age, <5% marrow blasts, low risk for leukemia transformation and in some studies hypocellularity (Lim et al., 2007; Sun et al., 2008). Among these factors, younger age is the most consistently linked clinical feature associated with IST responsiveness in both patients with aplastic anemia and in patients with MDS (Sun et al., 2008; Young, 2002). A model of immune pathogenesis first proposed by Molldrem et al suggests that unique or overexpressed antigens stimulate CD8+ T-cells, induce T-cell receptor (TCR) repertoire contraction through expansion of memory cells, and repress hematopoiesis through cross-reactive antigens expressed on normal bone marrow progenitors (Molldrem et al., 1998). In the subset of patients responsive to immunosuppression, effects of the self-reactive T-cell populations are thought to be eliminated by the immunosuppressive actions of these drugs (Molldrem et al., 1998; Kochenderfer et al., 2002).